Substrate and drug recognition mechanisms of SLC19A3  

作　　者：Yu Dang Tianyi Zhang Shabareesh Pidathala Guopeng Wang Yijie Wang Nanhao Chen Chen Song Chia-Hsueh Lee Zhe Zhang 

机构地区：[1]State Key Laboratory of Membrane Biology,Peking UniversityTsinghua University-National Institute of Biological Sciences Joint Graduate Program,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China [2]School of Life Sciences,Peking University,Beijing,China [3]Department of Structural Biology,St.Jude Children’s Research Hospital,Memphis,TN,USA [4]Cryo-EM Platform,School of Life Sciences,Peking University,Beijing,China [5]Center for Quantitative Biology,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China [6]Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China

出　　处：《Cell Research》2024年第6期458-461,共4页细胞研究（英文版）

基　　金：funded by the National Key R&D Program of China(2021YFA1302300 to Z.Z.);the National Natural Science Foundation of China(32171201 to Z.Z.);The study was also supported by the Center for Life Sciences School of Life Sciences of Peking University,the State Key Laboratory of Membrane Biology of China(to Z.Z.),and ALSAC(to C.-H.L.).

摘　　要：Dear Editor,Vitamins B,and Bo are two water-soluble vitamins.Their active forms thiamine pyrophosphate and pyridoxal 5'-phosphate serve as cofactors for numerous enzymes involved in multiple biochemical reactions that are essential to maintain the composition and energy metabolism of the human body.1 Consequently,their deficiency leads to a variety of diseases,such as neurological abnormalities'and cardiovascular diseases.?Humans cannot synthesize these vitamins de novo and must obtain them from the diet.Two specific transporters,thiamine transporter 1(ThTr1 or SLC19A2)and thiamine transporter 2(ThTr2 or SLC19A3),have been identified to be the major transmembrane transporters that are involved in the uptake of both vitamins thuse far3-Interestingly,the clinical antineoplastic drug fedratinib,a Janus kinase 2(JAK2)inhibitor used in treating myelofibrosis,induces Wernicke's-like encephalopathy in some myelofibrosis patients due to thiamine scarcityzs This is caused by its f-target inhibitory activity against both SLC19A2 and SLC19A3.°Here,we report the cryo-electron microscopy(cryo-EM)structures of human SLC19A3 in complex with vitamins Bi,B6,or fedratinib.Remarkably,all these compounds bind to the same site on SLC19A3 via a closely related structural element.Mutagenesis studies further revealed the critical residues of SLC19A3 for substrate and drug recognition.In summary,our work provides a structural framework for understanding the substrate diversity of SLC19A3.

关 键 词：VITAMIN METABOLISM SLC 

分 类 号：R96[医药卫生—药理学]